Members of the CREB/ATF family of transcription factors form dimers and bind to cyclic-AMP response elements found in a large number of cellular promoters. The diversity of genes regulated by this large group of transcription factors is reflected in the essential functions of individual factors in fetal survival, neurological development, bone growth, and immune system activation (Rudolph et al. 1998, Proc. Natl. Acad. Sci. USA, 95:4481-4486; Reimold et al. 1996, Nature, 379:262-265; Maekawa et al. 1999, J. Biol. Chem. 274:17813-17819). Recently, an important role in coordinating the timing of hepatocyte proliferation in the regenerating liver was demonstrated for the CREB/ATF family member CREM (Servillo et al 1998, Genes Dev. 12:3639-3643). In addition, the ATF-3 transcription factor was found to be induced in regenerating liver with the kinetics of an early response gene (Chen et al. 1996, Mol. Cell. Biol. 16:1157-1168).
The functions of a further CREB/ATF family member, XBP-1, have not been defined in detail. This transcription factor is expressed ubiquitously in adults but is mainly found in exocrine glands and bone precursors in the embryonic mouse (Liou et al. 1990, Science 247:1581-1584; Clauss et al. 1993, Dev. Dynamics 197:146-156). In vitro studies have demonstrated downregulation of the XBP-1 gene by BSAP, expression when antisense XBP-1 sequences are introduced into Raji cells (Reimold et al. 1996, J. Exp. Med., 183:393-401; Ono et al. 1991, Proc. Natl. Acad. Sci. USA 88:4309-4312). Recently, the expression of XBP-1 was found to be dramatically increased in hepatocellular carcinomas (Kishimoto et al. 1998, Cell Growth Diff. 9:337-344), although whether this upregulation played a role in the malignant phenotype, or was merely a by-product of it, was not established.